1. Field of the Invention
The invention relates to novel inhibitors of Type 3 17β-Hydroxysteroid Dehydrogenase, pharmaceutical compositions containing the compounds and the use of the compounds for the treatment or prevention of androgen dependent diseases.
2. Description of Related Art
Androgen dependent diseases, for example, diseases whose onset or progress is aided by androgenic activity, are well known. These diseases include but are not limited to prostate cancer, benign prostatic hyperplasia, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia and polycystic ovarian syndrome. Estrogen dependent diseases, i.e. diseases whose onset or progress is aided by estrogenic activity are also well known. These include but are not limited to breast cancer, endometriosis, leiomyoma and precocious puberty.
Androgenic and estrogenic activity may be suppressed by administering androgen receptor antagonists or estrogen receptor antagonists respectively. See e.g. WO 94/26767 and WO 96/26201. Androgenic and estrogenic activity may also be reduced by suppressing androgen or estrogen biosynthesis using inhibitors of enzymes that catalyze one or more steps of such biosynthesis. Type 3 17β-Hydroxysteroid Dehydrogenase (17β-HSD3) is the primary enzyme that converts androstenedione to testosterone in the testes. Androgenic and estrogenic activity may also be reduced by suppressing ovarian or testicular secretions by known methods. See e.g. WO 90/10462, WO 91/00731, WO 91/00733, and WO 86/01105. Type 5 17B-Hydroxysteriod Dehydrogenase is described in WO 97/11162. Novel inhibitors of both Type 3 and Type 5 17B-Hyroxysteroid Dehydrogenase are described in WO 99/46279.
U.S. Pat. No. 5,665,735 discloses compounds useful in the treatment of asthma, allergy and inflammation, which are of the formula: or a pharmaceutically acceptable salt or solvate thereof, wherein: or a five-membered heterocyclic aromatic group selected from the group consisting of Formulas I to XII:                 wherein X represents O, S.        
U.S. Pat. No. 5,432,175 discloses compounds which possess anti-allergic and anti-inflammatory activity and are of the formula: or a five-membered heterocyclic aromatic group containing at least one in the ring structure,                T represents CH, C or N,        
Current therapies for the treatment of androgenic and estrogenic dependent diseases include the use of glucocorticoids to block adrenal secretions, and luteinizing hormone releasing hormone (LHRH) agonists which cause medical castration. Both therapies are associated with undesirable side effects. An improved therapy would include compounds that specifically inhibit type 3 17β-Hydroxysteroid dehydrogenase, while avoiding inhibition of other 17β-Hydroxysteroid dehydrogenases. Such an improvement is provided by this invention.